The emergence of new metabolic pathways to overcome metabolic blocks poses a challenge for development of metabolic targeted drugs and construction of engineered microbes. Here, we demonstrate how endogenous metabolism can rewire to overcome metabolic blocks using few or no gain of function mutations. We use <i>Escherichia coli</i> as an example to investigate the strategies used by the cell. 39 mutant strains, incapable of growth in minimal media, were evolved using serial dilutions to yield 13 strains that escaped their auxotrophy. The underlying molecular mechanisms were elucidated for four of these strains, demonstrating 3 unique strategies: Recruitment of promiscuous enzymes, rewiring of a metabolic network, and gaining enzyme function to bridge untapped biochemistry. These examples demonstrate the ease by which cellular metabolism can adapt to overcome metabolic blocks and allude to challenges that may face development of metabolic targeted drugs.

Emerging metabolic pathways overcome metabolic blocks

254th National Meeting (2017)

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